Laura Mezquita1, Aurélie Swalduz2,3, Cécile Jovelet4, Sandra Ortiz-Cuaran3, Karen Howarth5, David Planchard1, Virginie Avrillon2, Gonzalo Recondo6, Solène Marteau2, Jose Carlos Benitez1, Frank De Kievit5, Vincent Plagnol5, Ludovic Lacroix4, Luc Odier7, Etienne Rouleau4, Pierre Fournel8, Caroline Caramella9, Claire Tissot10, Julien Adam11, Samuel Woodhouse5, Claudio Nicotra12, Edouard Auclin13, Jordi Remon14, Clive Morris5, Emma Green5, Christophe Massard6,12, Maurice Pérol2, Luc Friboulet6, Benjamin Besse1,6,15, Pierre Saintigny2,3. 1. Cancer Medicine Department, Gustave Roussy, Villejuif, France. 2. Department of Medical Oncology, Centre Léon Bérard Lyon, France. 3. Université de Lyon, Université Claude Bernard Lyon 1, INSERM U1052, CNRS UMR5286, Centre Léon Bérard, Cancer Research Center of Lyon, 69008 Lyon, France. 4. Plateforme de Génomique, Module de Biopathologie Moléculaire et Centre de Ressources Biologiques, AMMICa, INSERM US23/CNRS UMS3655, Gustave Roussy, Villejuif, France. 5. Inivata, Cambridge, United Kingdom. 6. INSERM U981, Gustave Roussy, Université Paris Saclay, Villejuif, France. 7. Department of Pneumology, Hôpital Nord-Ouest Villefranche, Villefranche Sur Saône, France. 8. Department of Medical Oncology, Institut de Cancérologie de la Loire, Saint-Priest-en-Jarez, France. 9. Radiology Department, Gustave Roussy, Villejuif, France. 10. Department of Pneumology, CHU Nord Saint-Etienne, Saint-Priest-en-Jarez, France. 11. Pathology Department, Gustave Roussy, Villejuif, France. 12. Early Drug Development Department, Gustave Roussy, Villejuif, France. 13. Medical Oncology Department, George Pompidou Hospital, Paris, France. 14. Hospital HM Delfos, Barcelona, Spain. 15. Paris-Sud University, Orsay, France.
Abstract
PURPOSE: Liquid biopsy specimen genomic profiling is integrated in non-small-cell lung cancer (NSCLC) guidelines; however, data on the clinical relevance for ALK /ROS1 alterations are scarce. We evaluated the clinical utility of a targeted amplicon-based assay in a large prospective cohort of patients with ALK/ROS1-positive NSCLC and its impact on outcomes. PATIENTS AND METHODS: Patients with advanced ALK/ROS1-positive NSCLC were prospectively enrolled in the study by researchers at eight French institutions. Plasma samples were analyzed using InVisionFirst-Lung and correlated with clinical outcomes. RESULTS: Of the 128 patients included in the study, 101 were positive for ALK and 27 for ROS1 alterations. Blood samples (N = 405) were collected from 29 patients naïve for treatment with tyrosine kinase inhibitors (TKI) or from 375 patients under treatment, including 105 samples collected at disease progression (PD). Sensitivity was 67% (n = 18 of 27) for ALK/ROS1 fusion detection. Higher detection was observed for ALK fusions at TKI failure (n = 33 of 74; 46%) versus in patients with therapeutic response (n = 12 of 109; 11%). ALK-resistance mutations were detected in 22% patients (n = 16 of 74) overall; 43% of the total ALK-resistance mutations identified occurred after next-generation TKI therapy. ALK G1202R was the most common mutation detected (n = 7 of 16). Heterogeneity of resistance was observed. ROS1 G2032R resistance was detected in 30% (n = 3 of 10). The absence of circulating tumor DNA mutations at TKI failure was associated with prolonged median overall survival (105.7 months). Complex ALK-resistance mutations correlated with poor overall survival (median, 26.9 months v NR for single mutation; P = .003) and progression-free survival to subsequent therapy (median 1.7 v 6.3 months; P = .003). CONCLUSION: Next-generation, targeted, amplicon-based sequencing for liquid biopsy specimen profiling provides clinically relevant detection of ALK/ROS1 fusions in TKI-naïve patients and allows for the identification of resistance mutations in patients treated with TKIs. Liquid biopsy specimens from patients treated with TKIs may affect clinical outcomes and capture heterogeneity of TKI resistance, supporting their role in selecting sequential therapy.
PURPOSE: Liquid biopsy specimen genomic profiling is integrated in non-small-cell lung cancer (NSCLC) guidelines; however, data on the clinical relevance for ALK /ROS1 alterations are scarce. We evaluated the clinical utility of a targeted amplicon-based assay in a large prospective cohort of patients with ALK/ROS1-positive NSCLC and its impact on outcomes. PATIENTS AND METHODS: Patients with advanced ALK/ROS1-positive NSCLC were prospectively enrolled in the study by researchers at eight French institutions. Plasma samples were analyzed using InVisionFirst-Lung and correlated with clinical outcomes. RESULTS: Of the 128 patients included in the study, 101 were positive for ALK and 27 for ROS1 alterations. Blood samples (N = 405) were collected from 29 patients naïve for treatment with tyrosine kinase inhibitors (TKI) or from 375 patients under treatment, including 105 samples collected at disease progression (PD). Sensitivity was 67% (n = 18 of 27) for ALK/ROS1 fusion detection. Higher detection was observed for ALK fusions at TKI failure (n = 33 of 74; 46%) versus in patients with therapeutic response (n = 12 of 109; 11%). ALK-resistance mutations were detected in 22% patients (n = 16 of 74) overall; 43% of the total ALK-resistance mutations identified occurred after next-generation TKI therapy. ALKG1202R was the most common mutation detected (n = 7 of 16). Heterogeneity of resistance was observed. ROS1 G2032R resistance was detected in 30% (n = 3 of 10). The absence of circulating tumor DNA mutations at TKI failure was associated with prolonged median overall survival (105.7 months). Complex ALK-resistance mutations correlated with poor overall survival (median, 26.9 months v NR for single mutation; P = .003) and progression-free survival to subsequent therapy (median 1.7 v 6.3 months; P = .003). CONCLUSION: Next-generation, targeted, amplicon-based sequencing for liquid biopsy specimen profiling provides clinically relevant detection of ALK/ROS1 fusions in TKI-naïve patients and allows for the identification of resistance mutations in patients treated with TKIs. Liquid biopsy specimens from patients treated with TKIs may affect clinical outcomes and capture heterogeneity of TKI resistance, supporting their role in selecting sequential therapy.
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